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Novel Pyrrolidine Diketopiperazines Selectively Inhibit Melanoma Cells via Induction of Late-Onset Apoptosis

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journal contribution
posted on 17.12.2015, 00:48 by Lillian Onwuha-Ekpete, Lisa Tack, Anna Knapinska, Lyndsay Smith, Gaurav Kaushik, Travis LaVoi, Marc Giulianotti, Richard A. Houghten, Gregg B. Fields, Dmitriy Minond
A common liability of cancer drugs is toxicity to noncancerous cells. Thus, molecules are needed that are potent toward cancer cells while sparing healthy cells. The cost of traditional cell-based HTS is dictated by the library size, which is typically in the hundreds of thousands of individual compounds. Mixture-based combinatorial libraries offer a cost-effective alternative to single-compound libraries while eliminating the need for molecular target validation. Presently, lung cancer and melanoma cells were screened in parallel with healthy cells using a mixture-based library. A novel class of compounds was discovered that selectively inhibited melanoma cell growth via apoptosis with submicromolar potency while sparing healthy cells. Additionally, the cost of screening and biological follow-up experiments was significantly lower than in typical HTS. Our findings suggest that mixture-based phenotypic HTS can significantly reduce cost and hit-to-lead time while yielding novel compounds with promising pharmacology.